Glucose is an important nutrient. During periods of moderate to heavy exercise, the muscles utilize large amounts of glucose to release energy. In addition, large amounts of glucose are taken up by muscle cells in the few hours after a meal. This glucose is stored in the form of muscle glycogen, and can later be used by the muscles for short periods of extreme use and to provide spurts or anaerobic energy for a few minutes at a time. Moreover, glucose is an essential nutrient for brain and spinal cord function. Glucose is the only nutrient that can normally be utilized by the brain, retina, and germinal epithelium of the gonads in sufficient quantity to supply those organs with their required energy. Brain tissue has an obligate requirement for a steady supply of blood glucose. When blood glucose levels fall below 50 mg/dl, memory loss, agitation, confusion, irritability, sweating, tachycardia, and hypertension commonly occur. Brain failure occurs when blood glucose levels fall below 30 mg/dl, and is associated with coma, hypoventilation, and vascular instability. Death may occur. Therefore, it is important to maintain the blood glucose concentration at a high enough level to provide this necessary nutrition.
At the same time, however, it is also important that the blood glucose concentration not rise too high. Glucose exerts a large osmotic pressure in the extracellular fluid. If glucose concentration rises to excessive levels, this can draw water out of the cells and cause considerable cellular dehydration. Excessively high blood glucose levels causes loss of glucose in the urine. This produces an osmotic diuresis by the kidneys, which can deplete the body of fluids and electrolytes.
The steady supply of blood glucose is tightly controlled by the pancreas and the liver. Following a meal, gastric digestion and intestinal absorption provide an increasing amount of carbohydrates, free fatty acids, and amino acids into the portal venous blood. Sixty percent of the glucose absorbed after a meal is immediately stored in the liver in the form of glycogen. Between meals, when the glucose concentration begins to fall, liver glycogen is dephosphorolated, allowing large quantities of glucose to diffuse out of the liver cells and into the blood stream. The liver, a large organ, can store six percent of its mass as glycogen. In contrast, muscle tissue can store only two percent of its mass as glycogen, barely enough to be used by the muscle as its own energy reserve.
Normally, blood glucose concentration is regulated by two hormones, insulin and glucagon, secreted by the pancreas. Insulin is released in a bimodal fashion from the pancreas in direct response to a rise in blood glucose level and, to a lesser extent, to a rise in the blood level of free fatty acids and amino acids. Insulin promotes transport of these nutrients into the cells to be utilized for energy, to be stored as glycogen or triglycerides, or to be synthesized into more complex compounds such as proteins.
Some individuals develop diabetes mellitus, and do not secrete insulin in sufficient quantities to properly regulate blood glucose. Lack of insulin inhibits the cell membrane transport of nutrients such as glucose, fatty acids, and amino acids into the cells, forcing the cells to use other compounds for energy and cell growth. Diabetics exhibit a decreased utilization of those nutrients by the cells, resulting in a marked increase in blood glucose concentration, an increase in triglyceride mobilization from the adipose tissue resulting in a marked increase in blood fatty acid and cholesterol concentrations, and a marked loss of protein on a cellular level. Most of the severe end-organ complications which result from diabetes are due to the cellular wasting which occurs secondary to abnormal amino acid uptake and protein wasting. Abnormal fatty acid metabolism results in elevated levels of blood concentrations of low-density lipoproteins (LDL), cholesterol, and free fatty acids, all leading to accelerated atherosclerosis and obstructive vascular disease. Those with diabetes are also prone to ketosis, and develop dehydration, acidosis, and electrolyte imbalance under stress. In some forms of the disease, insulin injections may be required, and other long-term complications such as retinopathy, blindness and kidney disease commonly occur.
The pancreas also secretes glucagon, a hormone which has cellular functions that are diametrically opposed to those of insulin. Glucagon stimulates the liver to release large amounts of glucose from glycogen when the blood glucose concentration falls below 90 mg/dl. This system of insulin inhibition and glycogen release prevents glucose concentrations from falling dangerously low.
In short, glucose is regulated within a narrow range between 80 and 90 mg/dl during fasting, with a rise toward 140 mg/dl following a high carbohydrate meal. The liver functions as a reservoir and buffer, so that glucose is available to the brain during meals and during periods of prolonged fast.
Type I diabetics have an absolute deficiency in insulin synthesis by the beta cells of the pancreas, and have the most severe clinical course if not aggressively managed with nutrition and insulin therapy. These individuals are ketosis prone and may develop a severe metabolic acidosis. Wide swings in blood glucose commonly occur with a high incidence of symptomatic hypoglycemia following insulin therapy. End organ dysfunction is common due to accelerated atherosclerosis, cellular protein wasting, and small vessel disease.
Type II diabetics release insulin from the pancreas in a blunted fashion following the intake of food. Blood insulin levels do not rise sufficiently to prevent hyperglycemia. In addition, peripheral tissues of type II diabetics may possess a smaller number of membrane tissue receptors and possibly a down regulation of those receptors. Ketoacidosis is uncommon. However, hyperglycemia and hyperosmolar conditions may occur, leading to coma and death. Insulin therapy may or may not be required to maintain normal glycemia levels. Other therapies include weight loss, diet, and oral hypoglycemic agents which stimulate the pancreas to release larger quantities of insulin.
There is no doubt that long term tight glucose control is able to significantly reduce the incidence of end organ complications. Control of blood glucose concentration in diabetic individuals by QID insulin injections has, of course, been done for many years. This type of treatment does have a number of serious drawbacks, however. One or more needle sticks of the finger must be performed on a daily basis to obtain blood for glucose assay. Many patients suffer anxiety and discomfort when subjected to finger pricking. After the blood sample is obtained, the sample must be exposed to a surface coated with chemical agents and enzymes that produce a color change corresponding to glucose concentration. The patient or medical practitioner performing the assay must interpret the color change accurately, and inject a dose of insulin based on the glucose level. Many individuals experience anxiety and discomfort when facing injections, and resist them. Some individuals may have no one to administer the required injections, but have difficulty injecting themselves. Dosage can also be problematic. Color change can be misinterpreted, and it is not unusual for patients to miss an injection, or to be off schedule. Syringes, which these days tend to be disposable, contribute to the growing problem of hazardous medical waste.
Some of these problems have been partially dealt with in the past, but none of the past attempts at dealing with these problems has been entirely satisfactory. Non-invasive optical techniques for measuring blood glucose have been developed, but these techniques do not solve the problems associated with administering insulin injections where required. Non-invasive optical techniques for measuring blood glucose are prone to error because the interface between the sensor and the tissue changes constantly with manipulation and contact pressure. Skin and extremity blood flow also varies considerably with cardiac output, body temperature and level of activity. These non-invasive optical techniques typically use a source of infrared (IR) radiation and a detector to measure absorption, reflection, or some other parameter to derive information about blood glucose levels. The effective optical distance from the IR source and the detector changes with subcutaneous body fat and the variability in placing the sensor from day to day. In addition, non-invasive IR sensors measure blood glucose in a non-continuous manner, and are thereby limited to functioning as a glucose measuring device and not as a therapeutic device for the treatment of diabetes.
Implantable pumps for administering insulin are known, and it has even been proposed to automatically measure blood glucose and administer insulin as may be required using an implantable sensor and insulin pump. However, the latter system uses a sensor which performs chemical analysis of blood samples, and thus requires the introduction of chemical reagents into the patient's body. In addition, the reagents periodically need to be replenished, which imposes the requirement of including a port below the surface of the skin through which fresh reagents must be injected from time to time. Thus, this system does not completely eliminate the need for periodic injections. The refilling process presents the danger of leaking a highly concentrated insulin solution into the body, which can result in severe hypoglycemia. Moreover, commercially available implantable pumps have FDA approval only for the infusion of chemotherapy and Baclofen for the treatment of spastic leg disorders. Pumps implanted for the infusion of insulin are still considered experimental.
An implantable sensor using a semipermeable membrane and an enzyme coated surface and oxygen electrode has been studied for the continuous measurement of blood glucose. This sensor has significant drift and quickly fails due to host reaction and contamination of the membrane and enzyme surface. Needle-type amperometric glucose sensors implanted within the subcutaneous tissues and having an enzyme coated surface and an electrical output to an external processor are known, but loss of sensitivity and sensor drift occur upon implantation. This type of sensor, which is in the form of a thin wire, must be inserted through a hollow needle into the subcutaneous tissue and must be changed every three to four days due to enzyme depletion and membrane contamination.
There is therefore a need to control levels of blood constituents, such as glucose concentration, fatty acid concentration, and amino acid concentration, in patients with diabetes which does not require blood sampling, chemical test reagents or reagent injections, and which provides continuous monitoring of levels of blood constituents. The present invention meets that need by providing a sensor which is fully implantable and can be used in vivo, can be used continuously and over the long term, and which is reliable and safe.
The present invention provides the ability to achieve close, continuous monitoring and control of insulin, which provides a clinical and therapeutic breakthrough.